The processes shown below are known as processes for preparing a substituted aromatic compound such as an aromatic halo compound through a transformation reaction of an aromatic diazonium salt from an aromatic amino compound.
A process for preparing a cyanobenzene derivative, comprising treating an aniline derivative (A) with a diazotization reagent and treating the benzenediazonium salt derivative (B) formed with a monovalent copper catalyst such as copper (I) cyanide (C-1) is based on a known Sandmeyer reaction or its analogous reaction (Sandmeyer-like reaction), as shown in the following scheme (see e.g., Patent References 1 to 2 and Non Patent References 1 to 5):
wherein X− represents the counter anion of the diazonium salt; and R0 represents a hydrogen atom or one or more substituents on the benzene ring.
Since the aromatic diazonium salt (B) obtained by the diazotization of aniline derivative (A) is generally an unstable and highly reactive intermediate, this well-known Sandmeyer reaction or its analogous reaction involves treating the aromatic diazonium salt (B) with a source material for substituents such as hydrogen chloride, hydrogen bromide, potassium iodide, sodium iodide, hydrogen cyanide, sodium cyanide, potassium cyanide, sulfuric acid, potassium sulfite, sodium sulfite, sodium bisulfate, sodium nitrite, potassium nitrite, hypophosphorous acid, or a hydroxyaryl derivative in the presence of a monovalent metal copper catalyst to prepare a substituted aromatic compound (D-2 to D-9) such as an aromatic cyano compound (D-1). In this context, hydrochloride, oxalate, sulfate, nitrate, perchlorate, tetrafluoroborate, hexafluorophosphate, or the like is used as a salt in the aromatic diazonium salt. Hydrochloride, oxalate, or tetrafluoroborate is generally used.
Alternatively, known processes for preparing the desired substituted aromatic compound (D) through a transformation reaction of an aromatic diazonium salt without use of a copper catalyst include: 1) a process for preparing a heteroaromatic halo compound from a heteroaromatic diazo compound in the presence of a source material for halogen such as hydrogen bromide without use of a copper catalyst; and 2) a process for preparing a heteroaromatic hydride compound from a heteroaromatic diazo compound in the presence of hypophosphorous acid without use of a copper catalyst (see e.g., Patent Reference 3).
Nitroxide radical compounds are known as organic free radicals that exist very stably. Such nitroxide radical compounds, typified by 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), represented by the following formula (5j):
are commercially available as organic synthetic reagents and are used as oxidation reagents, for example, for the oxidation of a primary alcohol into an aldehyde, in organic synthesis (see e.g., Non Patent References 6 to 8).
Use of a nitroxide radical compound in a Sandmeyer reaction or its analogous reaction has previously been reported only in the literature showing that in the course of studies on various conditions including copper catalysts and temperatures as to the synthesis of a halothiazole derivative from an aminothiazole derivative, the ratio and yield of products did not differ between the addition of a nitroxide radical compound 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) and the non-addition thereof (see e.g., Non Patent Reference 9). Thus, only a monovalent copper catalyst is a known catalyst that can promote a transformation reaction of an aromatic diazonium salt during a Sandmeyer reaction or its analogous reaction to prepare a substituted aromatic compound such as an aromatic cyano compound (D-1).
Meanwhile, a substituted aromatic compound prepared by a Sandmeyer reaction or its analogous reaction is often used as an intermediate for pharmaceutical preparation. Compounds shown below can be taken as an example.
A compound represented by the following formula (E) [hereinafter, also referred to as compound (E)]:
or a pharmacologically acceptable salt thereof or a hydrate thereof, is a compound that exhibits an FXa inhibitory effect, as disclosed in Patent References 4 to 6, and is useful as a preventive and/or therapeutic drug for thrombotic and/or embolic diseases (see e.g., Patent References 4 to 6). The thiazole derivative 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid (13) or a salt thereof is a compound that is important as an intermediate for preparation of FXa inhibitor compound (E) or a pharmacologically acceptable salt thereof, or a hydrate thereof, as shown in the scheme shown below (see e.g., Patent References 4 to 6).
For preparation of compound (13) or a salt thereof, its precursor bromide compound (11a) [compound represented by formula (11) in the scheme shown below wherein X10 is a bromine atom] or a salt thereof is important. A Sandmeyer reaction using a monovalent copper catalyst has been reported as a preparation method thereof (see e.g., Patent Reference 7). Alternatively, a copper catalyst-free method (see e.g., Patent Reference 8) has also been reported, but does not offer high reaction yields.
wherein X10 represents a halo group.